This interview first featured in Development.

Caroline Dean is a plant biologist based at the John Innes Centre in Norwich, UK. She helped to establish Arabidopsis as a model plant organism, and has worked for many years on the epigenetic mechanisms that regulate vernalisation, the process by which plants accelerate their flowering after periods of prolonged cold. We met Caroline at the recent Spring Meeting of the British Society for Developmental Biology. We asked her about her career, her thoughts on the plant field and being awarded this year’s FEBS EMBO Women in Science Award.

We are here at the Spring Meeting of the British Society for Developmental Biology. How are you finding the meeting?

This is not a meeting that I come to very often, but the questions asked here are always interesting because people think about my topic in a slightly different way. It’s always very interesting and illuminating to see what grabs people’s attention and what they get confused about.

This year you were awarded the FEBS EMBO Women in Science Award. What does receiving this prize mean to you, and what advice do you have for young female scientists?

I was thrilled to pieces! I heard on New Year’s Eve that I’d won it, so it was a great celebration that evening. It is a real honour because the women who have won this prize over the years are really fantastic scientists.

People have asked me how to encourage younger female scientists to break through the glass ceiling. There are still relatively few senior women scientists in Europe, although it’s not as bad as it used to be. My advice is to take the next obvious step at each stage of your career and not to worry too much about the long-term difficulties of a research career. When I started my career I didn’t have a clear goal, I didn’t aim to become a big leader in research. I just did research because I enjoyed it and found it an interesting topic. I really enjoyed being a graduate student and a postdoc, and now I really enjoy running a lab. So I would encourage young females to think “Yes, I can do it”, instead of worrying about “Well, can I achieve a work-life balance, can I compete in the current funding scenario, can I do this, can I do that?” I say to my postdocs “Jump, and then think!”

The nice thing about a science career is that it’s very flexible. As a PI you are your own boss, so if I needed to go off when the children were sick I did, and then caught up later. It’s not the type of job where you have to go in at set hours, so the flexibility helps enormously with the work-life balance. And children grow up very fast. There’s a lot of life left once they’ve left home!

Do you think role models, such as the women who have won this prize, are helpful?

I think role models do help. When I was a teenager my mother was the breadwinner, so for me the idea of a working mother was not unusual. At the John Innes Centre, I am involved in mentoring a number of project leaders and I also enjoy chatting to students and postdocs about research careers. I hope the younger scientists think “she managed to have a career and two kids who seem perfectly normal, and she is still quite into her science”, and that encourages them to continue.

How did you first become interested in biology? Was there someone who inspired you?

I loved the documentaries of the marine biologist Jacques Cousteau. I actually dragged my then boyfriend all the way down to Marseilles when I was 18 to see if I could meet him! Of course I didn’t, but I started off studying marine biology at university. I then discovered biochemistry, which I hadn’t really done at school. There was a particular plant biochemistry practical that I loved, where we isolated chloroplasts and did electron transport analysis. It really hooked me on lab work. I decided to be a technician so that I could continue doing lab work and after a year began a PhD – and it just rolled from there.

You did your undergraduate and PhD in the UK, but moved to California to do a postdoc in a biotech company. What was it like to work in industry?

The prospect of genetically modifying plants emerged when I finished my PhD, and venture capital funded a few start-up biotech companies. I did my postdoc in one of them, Advanced Genetic Sciences, in Oakland, California. The director, John Bedbrook (who came from academia), hired a bunch of academics. We had five years’ worth of money and our aim was to learn how to modify plants genetically and get foreign genes expressed in them. I learned all my molecular biology there. Very exciting times, because science was moving very quickly. So yes, it was a biotech company – but I could do fundamental academic research as part of the more biotech projects, e.g. generation of herbicide-tolerant plants. After five years, in 1988, I then moved back to the UK, to the John Innes Centre.

Your lab works on vernalisation. Why this scientific question?

When I was doing my postdoc in America, the Arabidopsis wave started – Elliot Meyerowitz and Chris Somerville initiated the use of a molecular genetic approach in Arabidopsis thaliana. I hadn’t done any such work while at the company, but I could see that this would open up analysis of really complex traits. For a trait like flowering time or developmental timing, we had no clue about which genes would be involved – you had to take a genetic approach. I chose to study vernalisation because of a conversation with a seller in a nursery garden in California. While I was buying some tulip bulbs he said to me “now put them in the fridge for six weeks before you plant them.” I was so intrigued that I looked it up: it turns out tulips need prolonged cold to flower in spring. I thought the whole ability of plants to monitor seasons was a really fascinating question. No one knew anything about molecular regulation of flowering time, let alone vernalisation, the acceleration of the flowering by cold that is very important for crop plants. Development of winter and spring varieties has significantly extended the geographical range of their production, but there was no molecular understanding of this trait. So I tackled that question using Arabidopsis genetics. I started this project in 1988 and we’re still doing it today!

We started off addressing different angles of the same question. Why do some plants need winter and others don’t? How does the plant actually remember that it has had winter? And how do plants cope with different lengths of winter? These research avenues all converged on a single regulator, a protein that blocks the transition to flowering: FLC. Whether you need winter or not depends on the expression level of that gene. Response to winter depends on epigenetically silencing that gene, and adaptation to different climates involves changes in that silencing mechanism.

The regulation of FLC involves conserved chromatin mechanisms, for example Polycomb silencing, and antisense RNAs. Subtle changes to the anti-sense transcripts are important to set the expression state, silence the gene or adapt to a different type of winter. It is a good system to understand the integration of many different layers of epigenetic regulation, which are often quite hard to dissect in other systems.

What are the next scientific questions that you would like to tackle?

I was lucky to be awarded a European Research Council grant to study how plants monitor and integrate fluctuating winter temperature. Plants integrate temperature changes over several weeks in order to monitor seasonal progression. I want to understand how they do that. What are the actual molecular thermosensors and how is their action channelled and integrated to regulate this one gene? We also want to understand how this process changes as plants adapt to different climates. These questions will be our focus over the next five years.

How has the use of Arabidopsis as a model system changed during your career?

Within the Arabidopsis community, there has been the development of very many extremely useful resources: genome sequences of 1000 natural accessions (there is a whole generation of students and postdocs that can’t remember what it was like doing science without a full genome sequence!); T-DNA collections knocking out all genes… Analysis of complex traits is now much faster in Arabidopsis. The scale of the international community also means you find things out by serendipity: you might think of a gene as flowering-specific and then find its mutation has been found in a completely different screen, which allows you to think of its function in a completely different way.

We need to fight the move for funders to think “let’s fund this reference plant for a bit, get the information we need and then concentrate on crop plants”. For example, flowering time is regulated by a variety of inputs: vernalisation, photoperiodicity, ambient temperature, metabolic signals. We are really quite a long way from understanding how all these fit together. We need to keep funding the basics to improve most rapidly our understanding of this complex adaptive trait – if we focus on flowering analysis in a few reference plants we will then be able to interpret experimental data on flowering in other species much faster. Gerry Fink, a yeast geneticist with an interest in Arabidopsis, made a very controversial statement in 1990: “If you want to understand wheat you should work on Arabidopsis, because four years of work on Arabidopsis will tell us more about wheat than working on wheat for four years.” We are still at the stage where it is very important to aim at a full understanding of how a whole plant works, responds to the environment and adapts. This is best done in reference plant systems at the same time as aiming to effectively translate this information into plant and crop biology as a whole.

At broad developmental biology meetings like this, there’s generally a very low representation of plant science. Would you like to see better integration between the plant and animal fields?

Plant science shouldn’t be seen as a poor relation. We should be very proud of what plant biology has contributed. If you look back at the history of biology, really fundamental discoveries – such as the concept of genetics, chromosomes, transposable elements, heterochromatin, small RNAs – have come from the plant field. Plant science should always be integrated into mainline biology. For example, our work has broad appeal because, although we are looking at a very plant-specific process, we have ended up studying epigenetic pathways that are widely conserved in eukaryotes. However, and this is true of many other communities, plant scientists tend to attend plant-specific meetings and publish in plant-specific journals, and this isolates them. I think it is good to reach beyond your own field. But fields operate using different languages, and this jargon (like the species-specific gene names) complicates comparisons. This is why it is quite good to have joint sessions as in this meeting.

What would people be surprised to find out about you?

I used to sail a lot before my children were born, but in the last few years my life has been a mosaic of family life and work. However, my children have now both gone to university, so I am thinking to myself that I need a hobby! Of course, when you don’t have a hobby what happens is that you work all the time. I am very privileged in that I really enjoy my job and I love being in touch with all that is going on in my lab!

(4 votes)

Loading...

Here are the highlights from the current issue of Development:

Probing gene expression dynamics in stem cells

The accurate control of gene expression is essential for cell differentiation during development but how do heterogeneous and fluctuating gene expression levels influence cell fate choices? Here (p. 2840), using a novel quantitative and high-content imaging platform, Jonathon Chubb and colleagues investigate how various cell- and population-based features are coupled to Nanog reporter expression in mouse embryonic stem cells (ESCs). They first show that cell cycle times are heterogeneous within ESCs but correlate with Nanog reporter expression; low expression levels are found in both long and short cell cycles but reporter expression tends to be highest in longer cycles. The transition to ground-state pluripotency (triggered by 2i treatment), they report, correlates with longer and more variable cell cycle times. Looking at lineage history, the researchers further reveal that all cells within a lineage are strongly related with regards to both cell cycle times and reporter expression. Modelling further suggests that some element of the cell environment plays a role in stabilising gene expression between generations. Finally, the researchers highlight a correlation between cell density and both cell cycle behaviour and reporter gene expression. Based on these and other findings, the authors propose that simple deterministic views of stem cell states need rethinking.

Fattening up neural development

Fat family atypical cadherins are known to regulate planar cell polarity and growth control in Drosophila. In mammals, four Fat genes (Fat1 to Fat4) have been identified but relatively little is known about how these regulate mammalian embryogenesis. Here, Helen McNeill and co-workers identify a role for Fat proteins in regulating various aspects of brain development in mice (p. 2781). Using mutant mice, the researchers first identify a role for Fat1 in neural tube closure; Fat1mutants display cranial neural tube closure defects leading to exencephaly. They further show that the cortex of these mutant embryos exhibits elongated ventricles, linked to an increase in radial precursor cell proliferation. Accordingly, the knockdown of Fat1 by in utero electroporation in the developing cortex causes an increase in radial precursor cell proliferation and perturbs neuronal differentiation and migration. The researchers further show that Fat4 interacts genetically with Fat1 to control these processes. Finally, they reveal that Fat1 and Fat4 bind to distinct sets of actin regulators and apical junction proteins, respectively. Together, these findings lead the authors to propose a model in which Fat1-Fat4 dimer formation brings together diverse proteins at apical junctions to regulate both apical constriction and progenitor cell divisions in the neural tube.

Tissue regeneration: from Hippo to flies and fish

The Hippo pathway, best known for its role in growth control, has been implicated in tissue repair and regeneration in various contexts. In this issue, two papers provide insights into how Hippo signalling regulates tissue growth during regeneration.

In the first report (p. 2740), Joy Meserve and Robert Duronio study the Drosophila eye to investigate the mechanisms that allow quiescent cells to re-enter the cell cycle and proliferate in response to tissue damage. Using an RNAi screen, they reveal that scalloped (sd), which encodes a transcriptional effector of the Hippo pathway, is required for compensatory proliferation following tissue damage. They demonstrate that Sd and its binding partner Yorkie (Yki) are required to induce Cyclin E expression and hence drive S-phase entry in regenerating eye discs. The researchers further show that Ajuba (Jub), an upstream regulator of Hippo signalling, is needed for cell cycle re-entry. Given the roles of Jub in sensing epithelial integrity, the authors propose that the apoptotic force induced by tissue damage in this context triggers Jub and Sd/Yki activation that, in turn, allows for compensatory proliferation and tissue repair.

In a second paper, Antonio Jacinto and colleagues reveal a role for the Hippo pathway effector Yap in zebrafish fin regeneration (p. 2752). Fin regeneration involves three steps – wound healing, blastema formation and tissue outgrowth – and the researchers show that Yap activation (and hence nuclear localisation) is dynamic during these steps. Yap is nuclear during wound healing, remains nuclear during blastema formation, and then is cytoplasmic in regions distal to the wound but nuclear in proximal regions during outgrowth. They further show, by modulating Yap levels, that Yap regulates cell proliferation and the expression of key regeneration factors. The researchers also report that Yap localisation correlates with changes in cell density and cell morphology along the blastema proximal-distal axis. Finally, they observe similar gradients in α-catenin and F-actin localisation, suggesting a model in which a mechanotransduction process involving changes in cell morphology, junctional assembly and the cytoskeleton controls the activation of Yap to regulate tissue regeneration.

PLUS:

An interview with Caroline Dean

Caroline Dean is a plant biologist based at the John Innes Centre in Norwich, UK, who works on the epigenetic mechanisms that regulate vernalisation. We talked to Caroline about her career, her FEBS EMBO Women in Science Award, and her thoughts on the plant field. See the Spotlight article on p. 2725

The embryo reunited with its membranes in Göttingen

In this meeting review, Claudio Stern summarises the work and advances presented at the recent EMBO Workshop ‘Embryonic-Extraembryonic Interfaces’, which took place in Germany. See the Meeting Review on p. 2727

Primordial germ cells: the first cell lineage or the last cells standing?

In this Hypothesis article, Johnson and Alberio propose that the determinative mechanisms for PGC specification in most model systems evolved to promote speciation and evolvability, not to maintain the germ line. See the Hypothesis on p. 2730

(No Ratings Yet)

Loading...

Last month I attended the SDB annual meeting in Utah, an excellent conference that featured great scientific talks and additional educative sessions covering outreach, inclusiveness and more. I tweeted extensively from the Node’s twitter account, but as many of the readers of the Node are not on twitter, I realised that you may have missed out on some of the great advice shared at the meeting. So here is the roundup of some the thoughts and recommendations shared at the conference!

On progressing your scientific career:

Brigid Hogan was awarded this year’s SDB Lifetime Achievement Award, and gave a great talk on her life and career so far, and the lessons she learnt along the way:

• You have to take risks if you want to follow your passion and do something important.
• Seek out people who will give you criticism, even if it is difficult. It will help you do better.
• Share the resources (reagents and ideas) you have generated. It will help you know people and they will share their resources with you.
• Be confident in your own results.
• Find good role models, not just for how you do science but also on how to deal with important social issues.
• Have your 2 minute elevator speech ready. You never know when it will come handy! (read our interview with Brigid for her account of how a well-timed 2 minute speech helped her establish the CSH course on mouse embryology).
• Never go to a organisational/administrative meeting unprepared. Form your coalitions beforehand.
• Trust your own scientific judgement and seek impartial advice when making a career move.
• Interactions with clinicians can be very rewarding.
• Keep embracing new technologies and apply them to your system. One of the best ways to keep up with what’s new is to attend meetings.
• Publish, publish, publish- stories are never complete and others will find your data useful

Kathryn Tosney was the winner of the Viktor Hamburger Outstanding Educator Prize, and gave a varied talk that ranged from her work on growth cones to her recent iguana preservation project. During her career she has been involved in many aspects of mentoring, and here are some of her thoughts:

• Descriptive has become a bad word in science, but it’s essential to frame your question. Looking is important.
• Advice to postdocs- don’t assume you can take your project with you when you start your own lab. This will have to be negotiated with your PI.
• Advice for new assistant professors (echoing Brigid’s thoughts)- write your papers as you go along, and publish early. Early publications help to establish that you are respected, independent and productive.
• Good letters from prominent supporters are key for promotion.
• Presenting a good poster is important to make connections. Write a good title that states the result and why is important
• In science the workload is too high, the pay is too low, it can be frustrating… It can’t just be a job, must be a passion!

On communicating your science

One of the additional sessions on the conference was the education symposium, where the do’s and don’ts of science communication (at many levels) were discussed. Chanda Jefferson is teacher who won this year’s South Caroline Biology Teacher of the Year award. She told the audience what teachers need from scientists:

• Give your research a hook- something to remember. E.g. the title of Bonnie Bassler’s TED talk on quorum sensing is a great hook: ‘How do bacteria talk?’- this is something that gets the students interested!
• Make research fun- what is the coolest, the grossest bit of your research? Turn it into a story.
• Make your work relevant to students, generalise to something they can relate to.
• Develop data-based activities: give your own data to the class to analyse, help teachers develop practical lab activities.

In the same session Karen Weintraub, a freelance journalist, talked about what journalists need from scientists when they are writing a story:

• Speak English, not science. And don’t be condescending- journalists are not idiots, they just aren’t specialists in your field
• Share your passion for the work- don’t assume it is obvious.
• Put your work in a broader context. Don’t exaggerate your findings but don’t underplay them either.
• Pretty images make your research easier to understand, and are more likely to get visibility.
• Use metaphors and analogies.
• It is good to have notes, but don’t just read what you wrote. A good interview is a conversation between the journalist and the scientist.
• Sharing personal details and experiences may be uncomfortable, but helps the public connect and care about the research.
• Journalists are just as intimidated by you as you are by them!
• Journalists are under pressure and over-worked. They need your help to write the best story that they can!

What good advice (on this or other topics) was shared at recent meetings you have attended? Leave a comment here and share it with the rest of the community!

(1 votes)

Loading...

Here is August’s round-up of some of the interesting content that we spotted around the internet!

News & Research

– Ian Sussex, one of the founding fathers of plant developmental biology, recently passed away. Developmental Biology published an obituary.

– Nature jobs published several articles providing advice to new PIs: how to manage your lab budget, to serve (or not to serve) in committees, and the testimony of Samantha Morris, who has just successfully applied for her first PI position. Steve Royle also shared his tips.

– ‘Pay very careful attention to unexpected results’- Shinya Yamanka shared his thoughts in Science Careers.

– The organoids boom and what they are teaching us about human development- in Nature.

– The first iPSC clinical has been halted due to genomic issues. Paul Knoepfler covered this story here and here.

– Do biases keep LGBT scientists from coming out? Nature investigates.

– Thinking about leaving the lab? The first step is to know yourself.

– And the LMB sponsored an online exhibition on the life and work of Fred Sanger.

Weird & Wonderful

– London is currently hosting a series of DNA sculptures, to raise funds for CRUK. Do the DNA trail to see them all!

– The winning image of this year’s Wellcome Trust Image Awards was a pregnant pony uterus. This video shows some of the other similar historical specimens housed at the Royal Veterinary College in London.

– Which 10 scientists would you want by your side in a bar brawl? Here’s a potential list!

– And here is the human body reimagined as a metro map!

This is great! Reimagining the human #body as a tube #map [Image: Sam Loman] http://t.co/1KKdqLQkBA RT@qikipedia pic.twitter.com/Y1ptBYQu4x

— MaxPlanck-Innovation (@MP_Innovation) July 27, 2015

Beautiful & Interesting images:

– There are a lot of interesting shapes hidden in histology samples (as this twitter account attests!). How about this histology T-Rex?

– The MBL Woods Hole embryology course 2015 class decided to reproduce an historical course photo from 1893. Compare the two!  

1893-2015: another thread permanently sewn to the Embryology Course tapestry #embryo2015 @MBLScience @___SDB___ pic.twitter.com/zbX7M6PU7o

— A. Sánchez Alvarado (@Planaria1) July 19, 2015

Videos worth watching:

– Here’s a cool video showing the neural activity in a Drosophila brain. From a recent Nature Communications paper.

– And we found this fabulous movie of Xenopus development, by Nipam Patel

Keep up with this and other content, including all Node posts and deadlines of coming meetings and jobs, by following the Node on Twitter

(1 votes)

Loading...

The protein E-Cadherin (E-Cad) is a kind of adhesive that keeps cells tightly bound together, thus favouring the organisation of tissues and organs. Scientists at the Institute for Research in Biomedicine (IRB Barcelona) now reveal a new function for E-Cad, one that contrasts with its accepted role in impeding cell movement. The researchers have published an article in Nature Communications in which they report that this protein is crucial for the coordinated movement of diverse cell types.

This new function of E-Cad may explain why tumours that express intermediary levels of this protein have a poorer prognosis.

Coordinated cell movement

E-Cad facilitates the movement of heterogeneous groups of cells—understanding as heterogeneity cells that exert a range of activities because they have different genes activated: some may divide many times, others trigger certain hormones, while others interact with the membrane, etc…

Thanks to E-Cad, this group of diverse cells moves in a coordinated manner to its destination. Once there, the cells distribute where they are needed; their moderate levels of E-Cad keep them bound but not immobile during this migration. IRB Barcelona researchers Kyra Campbell and Jordi Casanova have addressed this phenomenon in the development of the embryonic digestive system of the fly Drosophila melanogaster, a model that allows them to study cell migration in a growing organism.

“Cell migration is a common and necessary process for an embryo and also for the correct function of the adult organism. What has been most surprising is the observation that E-Cad is a key component in cell movement, when its role was previously assumed to be that of keeping cells static,” explains Jordi Casanova, head of the Development and Morphogenesis in Drosophila Lab at IRB Barcelona and CSIC research professor.

Cell migration is also of great biomedical relevance, and research into this phenomenon sheds light on how, for example, cancer metastasis and other processes such as wound healing and inflammation arise.

Cell migration and metastasis

According to Casanova, intermediary levels of E-Cad are often associated with aggressive tumours, precisely those which are capable of metastasising. He also reveals that, “the more we learn about metastases, the more evidence emerges that they are formed by groups of cells and not by individual ones”.

E-Cad would facilitate highly diverse heterogeneous groups of cells to migrate together from the original tumour. “A cell that migrates alone is much easier to eliminate that a group of cells with different functions,” explains the researcher.

“Our results in Drosophila are clinically relevant because they offer an explanation of the role that may be played by E-Cad in tumours with metastasis,” says Casanova.

The study has involved the participation of researchers from Advanced Digital Microscopy Core Facility at IRB Barcelona, headed by Julien Colombelli. Sébastien Tosi, Senior Research Officer with this facility, set up the programmes to monitor cells in vivo during their migration.

Reference article:

A role for E-Cadherin in ensuring cohesive migration of a heterogeneous population of non-epithelial cells

Kyra Campbell and Jordi Casanova

Nature Communications (14 August 2015): DOI: 10.1038/ncomm8998

This article was first published on the 14th of August 2015 in the news section of the IRB Barcelona website

(No Ratings Yet)

Loading...

A postdoctoral position is available to study the mechanisms regulating skeletal development and their relationship to skeletal birth defects using mouse models, molecular biology, and next-generation sequencing. Highly motivated candidates who recently obtained a Ph.D. and have a strong background in developmental biology are encouraged to apply. Preference will be given to those with model organism experience who have a first-author publication as a result of their graduate work. Interested candidates should send their CV, a brief description of their research, and names of three references to:

Amy E. Merrill. Ph.D. (amerrill@usc.edu)

Center for Craniofacial Molecular Biology

University of Southern California

https://dent-web10.usc.edu/ccmb/faculty_detail.asp?RS=80#

(No Ratings Yet)

Loading...

Funds, especially for travel have been tightly squeezed in recent times and here at Abcam we know of how difficult it is for scientists, especially those starting out in their careers to attend conferences. Abcam is committed to bringing scientists together to share information, strengthen relationship and forge new collaborations.

With this ethos, we’re very pleased to offer travel grants to people wishing to attend the Epigenetics, Obesity & Metabolism conference on 11-14 October 2015 at the Wellcome Genome Campus Conference Centre in Hinxton, Cambridge, UK.

This meeting will brings together key scientists from around the world to discuss:

– Epigenetics, metabolism and the links with circadian rhythms
– Early developmental origins of metabolic disorders
– Epigenetic linkages between nutrition and longevity
– Transgenerational consequences of metabolic dysfunction
– Mechanisms of signalling to the epigenome and inheritance

View program

Each grant is valued up to £300 (GBP) each and are available to students and young postdocs (who have received their PhD within the last 4 years). Grants can be used to help cover travel and accommodation expenses associated with the conference.

Application deadline: 1 September 2015

More information including how to apply can be found at www.abcam.com/EOM2015.

We hope you see you there!

(No Ratings Yet)

Loading...

My lab works on developmental bioelectricity, studying how cells communicate via endogenous gradients of plasma membrane resting potential (Vmem) in order to coordinate their activity during pattern regulation (Levin, 2013; Levin, 2014b; Tseng and Levin, 2013). It is well-known that resting potential is an important regulatory parameter for individual cells’ proliferation, differentiation, and oncogenic potential (Blackiston et al., 2009; Sundelacruz et al., 2009). Voltage itself is an important “master control knob” because the same morphogenetic phenotype (e.g., inducing eye formation or metastatic conversion) can be induced by using sodium, potassium, chloride, or even proton flows to achieve a particular Vmem level. The chemical nature of the ion (and the genetic identity of the channel) often does not matter, as long as the voltage gradient is established correctly for a particular downstream outcome. In this Node post, I wanted to briefly mention a few of our recent studies which highlight an exciting new aspect of this field: long-range signaling via gap junctions.

Gap junctions (GJs) are electrical synapses – direct conduits for small molecules between cells, which can be used to form isoelectric compartments in vivo; they have numerous roles in normal development and disease (Levin, 2007; Sohl and Willecke, 2004; Wong et al., 2008). Most importantly, they are extremely versatile signaling elements (Palacios-Prado and Bukauskas, 2009; Pereda et al., 2013), because they both regulate cellular resting potential and are themselves voltage-gated.  GJs are able to function as a kind of transistor, allowing voltage to control current flow. Because they are ideally-suited to process information in physiological cell networks, is no surprise that gap junctional communication is a key regulator of brain activity, developmental patterning, and carcinogenesis.

One of our recent studies investigated the role of endogenous bioelectric gradients in brain formation in the Xenopus laevis embryo (Pai et al., 2015). Early frog embryos exhibit a characteristic hyperpolarization of cells lining the neural tube; disruption of this spatial gradient of the transmembrane potential (Vmem ), using misexpression of depolarizing channels, diminishes or eliminates the expression of early brain markers, and causes anatomical mispatterning of the brain. Conversely, forced establishment of the brain-specific voltage pattern (using expression of select ion channels) was able to rescue brain defects induced by mutant Notch protein (a potent regulator of neurogenesis), and even induce ectopic brain tissue in posterior regions of the tadpole.

In addition to cell-autonomous effects, we showed that hyperpolarization of transmembrane potential (Vmem ) in ventral cells, well-outside the brain, induced upregulation of neural cell proliferation. These long-range effects were mediated by gap junctional communication, and another recent paper extended such long-range regulation of cell division to similar non-local control of apoptosis (Pai, 2015). We suggested a model in which brain cells coordinate growth and sculpting decisions with the remaining tissues (to determine appropriate location, size, and boundaries of the nascent brain) via electrical signals mediated by GJ paths.

Interestingly, a similar story was found for tumorigenesis in Xenopus (Chernet et al., 2014). mRNA encoding mutant KRAS induces tumors in a zebrafish cancer model (Le et al., 2007). We showed that the same thing happens in Xenopus (complete with induced angiogenesis, overproliferation, expression of tumor markers, and immune response); remarkably, a specific bioelectric state of cells at a considerable distance (on the other side of the body) can suppress tumor formation, despite strong expression of the oncogene. The effect is mediated by butyrate signaling (Chernet and Levin, 2014), which links voltage regulation to chromatin modification, and – GJs. These data are part of a growing body of evidence (Bizzarri and Cucina, 2014; Chernet and Levin, 2013; Soto and Sonnenschein, 2011; Tarin, 2011) highlighting aspects of cancer as a “disease of geometry” – a disorder of patterning cues and cell:cell communication that normally harnesses cell activity towards specific morphogenetic goals and away from tumorigenesis.

It appears that in diverse contexts, such as embryonic establishment of pattern and tumor suppression, GJs link bioelectric and biochemical pathways to regulate events at considerable distance. Thus, future work must focus not only on ever-more detailed dissection of biophysical signaling events within single cells, but also address group dynamics and large-scale emergent properties of physiological networks linked by electrical synapses (Donnell et al., 2009; Levin, 2014a; Saraga et al., 2006; Schiffmann, 2008; Steyn-Ross et al., 2007). Multicellular models of GJ signaling will surely contribute to the understanding of patterning and deviations from normal growth and form.

References

Bizzarri, M. and Cucina, A. (2014). Tumor and the microenvironment: a chance to reframe the paradigm of carcinogenesis? Biomed Res Int 2014, 934038, http://www.ncbi.nlm.nih.gov/pubmed/25013812

Blackiston, D. J., McLaughlin, K. A. and Levin, M. (2009). Bioelectric controls of cell proliferation: ion channels, membrane voltage and the cell cycle. Cell cycle (Georgetown, Tex 8, 3519-3528, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19823012

Chernet, B. and Levin, M. (2013). Endogenous Voltage Potentials and the Microenvironment: Bioelectric Signals that Reveal, Induce and Normalize Cancer. J Clin Exp Oncol Suppl 1, http://www.ncbi.nlm.nih.gov/pubmed/25525610

Chernet, B., and Levin, M., (2014), “Transmembrane voltage potential of somatic cells controls oncogene-mediated tumorigenesis at long-range”, Oncotarget, 5(10): 3287-3306

http://www.ncbi.nlm.nih.gov/pubmed/24830454

Chernet, B. T., Fields, C. and Levin, M. (2014). Long-range gap junctional signaling controls oncogene-mediated tumorigenesis in Xenopus laevis embryos. Front Physiol 5, 519, http://www.ncbi.nlm.nih.gov/pubmed/25646081

Donnell, P., Baigent, S. A. and Banaji, M. (2009). Monotone dynamics of two cells dynamically coupled by a voltage-dependent gap junction. Journal of theoretical biology 261, 120-125, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19627994

Le, X., Langenau, D. M., Keefe, M. D., Kutok, J. L., Neuberg, D. S. and Zon, L. I. (2007). Heat shock-inducible Cre/Lox approaches to induce diverse types of tumors and hyperplasia in transgenic zebrafish. Proc Natl Acad Sci U S A 104, 9410-9415, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17517602

Levin, M. (2007). Gap junctional communication in morphogenesis. Prog Biophys Mol Biol 94, 186-206, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17481700

Levin, M. (2013). Reprogramming cells and tissue patterning via bioelectrical pathways: molecular mechanisms and biomedical opportunities. Wiley Interdisciplinary Reviews: Systems Biology and Medicine 5, 657-676, http://www.ncbi.nlm.nih.gov/pubmed/23897652

Levin, M. (2014a). Endogenous bioelectrical networks store non-genetic patterning information during development and regeneration. The Journal of Physiology 592, 2295-2305, http://jp.physoc.org/content/592/11/2295.abstract

Levin, M. (2014b). Molecular bioelectricity: how endogenous voltage potentials control cell behavior and instruct pattern regulation in vivo. Mol. Biol. Cell 25, 3835-3850, http://www.ncbi.nlm.nih.gov/pubmed/25425556

Pai, V. P., Lemire J. M., Chen Y., Lin G., and Levin M. (2015). Local and long-range endogenous resting potential gradients antagonistically regulate apoptosis and proliferation in the embryonic CNS. Int. J. Dev. Biol., in press

Pai, V. P., Lemire, J. M., Pare, J. F., Lin, G., Chen, Y., & Levin, M. (2015). Endogenous Gradients of Resting Potential Instructively Pattern Embryonic Neural Tissue via Notch Signaling and Regulation of Proliferation Journal of Neuroscience, 35 (10), 4366-4385 DOI: 10.1523/JNEUROSCI.1877-14.2015

Palacios-Prado, N. and Bukauskas, F. F. (2009). Heterotypic gap junction channels as voltage-sensitive valves for intercellular signaling. Proc Natl Acad Sci U S A 106, 14855-14860, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19706392

Pereda, A. E., Curti, S., Hoge, G., Cachope, R., Flores, C. E. and Rash, J. E. (2013). Gap junction-mediated electrical transmission: regulatory mechanisms and plasticity. Biochimica et biophysica acta 1828, 134-146, http://www.ncbi.nlm.nih.gov/pubmed/22659675

Saraga, F., Ng, L. and Skinner, F. K. (2006). Distal gap junctions and active dendrites can tune network dynamics. J. Neurophysiol. 95, 1669-1682, http://www.ncbi.nlm.nih.gov/pubmed/16339003

Schiffmann, Y. (2008). The Turing-Child energy field as a driver of early mammalian development. Prog Biophys Mol Biol 98, 107-117, http://www.ncbi.nlm.nih.gov/pubmed/18680762

Sohl, G. and Willecke, K. (2004). Gap junctions and the connexin protein family. Cardiovasc Res 62, 228-232, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15094343

Soto, A. M. and Sonnenschein, C. (2011). The tissue organization field theory of cancer: a testable replacement for the somatic mutation theory. Bioessays 33, 332-340, http://www.ncbi.nlm.nih.gov/pubmed/21503935

Steyn-Ross, M. L., Steyn-Ross, D. A., Wilson, M. T. and Sleigh, J. W. (2007). Gap junctions mediate large-scale Turing structures in a mean-field cortex driven by subcortical noise. Phys Rev E Stat Nonlin Soft Matter Phys 76, 011916, http://www.ncbi.nlm.nih.gov/pubmed/17677503

Sundelacruz, S., Levin, M. and Kaplan, D. L. (2009). Role of membrane potential in the regulation of cell proliferation and differentiation. Stem cell reviews and reports 5, 231-246, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19562527

Tarin, D. (2011). Cell and tissue interactions in carcinogenesis and metastasis and their clinical significance. Semin Cancer Biol 21, 72-82, http://www.ncbi.nlm.nih.gov/pubmed/21147229

Tseng, A. and Levin, M. (2013). Cracking the bioelectric code: Probing endogenous ionic controls of pattern formation. Communicative & Integrative Biology 6, 1-8, http://www.landesbioscience.com/journals/cib/article/22595/

Wong, R. C., Pera, M. F. and Pebay, A. (2008). Role of gap junctions in embryonic and somatic stem cells. Stem Cell Rev 4, 283-292, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18704771

(2 votes)

Loading...

First Announcement
The 16th International Xenopus Conference
Sunday 28 August – Thursday 1 September, 2016
Venue: Orthodox Academy of Crete, Chania

^{_{Please join us for the 16th International Xenopus Conference to be held 28 August – 1 September 2016 at the Orthodox Academy of Crete. This conference has been held biennially since 1984 and brings together researchers from diverse fields, all of whom use Xenopus as a model system. The format of the conference provides outstanding opportunities for scientific exchange with over three hundred poster presentations and talks. In particular, junior faculty are encouraged to speak. There will also be numerous opportunities for postdocs and students to present their work and participate in career development activities. Finally, this meeting has traditionally been an ideal forum to learn about the latest technological advances and resources in the Xenopus system.}}

^{_{Xenopus as a model system spans many fields, including subjects such as cell cycle and cytoskeletal regulation, developmental biology and stem cells, immunology, neurobiology and systems biology. This diversity of topics is a major advantage of the Xenopus community, and this meeting seeks to highlight and reinforce these interdisciplinary interactions.}}

^{_{For this meeting, we expect over 50 talks and 200 posters, as well as plenary sessions, with an outstanding line up of speakers from around the world.}}

^{_{Check back regularly at the website for updates about the conference, including information on registration, abstract submission, the scientific and social programme as well as details of our sponsors and exhibitors, whose essential support and contribution to the conference are very much appreciated.}}

^{_{We hope you can join us and look forward to welcoming you to Crete on 28 August to 1 September, 2016.}}

Important Dates

Registration opens – November, 2015
Abstract submission opens – November, 2015
Deadline for early bird registration fee – 10 June, 2016
Abstract submission deadline – 05 May, 2016
Pre-registration deadline – 12 August, 2016

Organising Committee

Josh Brickman
Karen Liu
Viki Allan
Matt Guille
Grant Wheeler

Please visit the conference website for further information: http://www.xenopus16.com

Please note that the website will continue to be updated with new information so please check back regularly.

(2 votes)

Loading...

The Department of Developmental Biology at Washington University School of Medicine invites applications for a Biomedical Informatics Assistant. The Department of Developmental Biology is a dynamic research community, with interests spanning multiple model organisms and disease paradigms.

We are seeking an outstanding applicant to join at the level of Biomedical Informatics Assistant to provide bioinformatics expertise and develop data analysis pipelines. The applicant is expected to have a B.A./B.S. or M.S. in a relevant area, including, but not limited to, computer science, statistics, and biology. Knowledge of developmental biology and/or regenerative medicine would be a plus. The successful candidate will report to the head of the Bioinformatics Research Core (http://brc.wustl.edu/) and assist on fundamental next generation sequencing analysis (ChIP-seq, RNA-seq, genome/exome sequencing), utilizing state of the art bioinformatics tools. Additional duties include the development of pipelines and novel analysis software. Proficiency with statistics and common scripting languages and analysis tools (e.g., Perl, R, and/or Python) is expected. In addition, the candidate should have excellent writing, communication and interpersonal skills. This is an excellent opportunity to gain additional experience with biomedical data analysis, interact with multiple research paradigms, and author scientific publications.

Review of applications will start September 1, 2015. Interested applicants should email a single PDF file consisting of a cover letter and curriculum vitae, and should arrange for submission of three letters of reference to:

Biomed Informatics Search Committee (c/o Bo Zhang, Ph.D.)

Department of Developmental Biology

Washington University School of Medicine

660 South Euclid Avenue, Campus Box 8103

St. Louis, MO 63110

Email: devbiosearch[at]wustl.edu

Washington University is an Equal Opportunity Employer AA/EOE M/F/D/V.

(No Ratings Yet)

Loading...